Duloxetine is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It has application for the treatment of stress urinary incontinence (SUI), depression, and pain management. Duloxetine hydrochloride has the following chemical name: (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloric acid salt and the structure:

Duloxetine base, as well as processes for its preparation, is disclosed in U.S. Pat. No. 5,023,269 (U.S. '269). EP patent no. 457559, and U.S. Pat. No. 5,491,243 (U.S. '243) and U.S. Pat. No. 6,541,668 provide an improved synthetic route for the preparation of duloxetine base.
The preparation of the enantiomerically pure duloxetine intermediate (S)-AT-OL by its chiral resolution is exemplified in U.S. Pat. No. 5,362,886 (U.S. '886) and in WO 2004/031168, by the use of (S)-(+)-mandelic acid and (−)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid, respectively. The U.S. '886 patent describes the preparation of duloxetine by the chiral resolution of N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine (rac-AT-OL) with (S)-mandelic acid (Stage a), its reaction with fluoronaphtalene (Stage b) to give N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (DNT), demethylation with phenyl chloroformate (Stage c), basic hydrolysis in the presence of (Stage d), and acidification (Stage e) in accordance with the following Scheme 1.

In U.S. Pat. No. 5,362,886, a process for chiral resolution of (S)-AT-OL is disclosed where a reaction mixture is substantially worked-up, and then combined with MTBE (methyl t-butyl ether) and concentrated. The concentrated MTBE containing reaction mixture is then combined with (S)-(+)-mandelic acid in ethanol at 50° C., followed by recovery of the mandelate. The process of this patent does not attempt to recycle the (R)-AT-OL remaining in the mother liquor.
US '269 describes the preparation of enantiomerically pure (S)-AT-OL by its chiral resolution of the racemic N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine (rac-AT-OL) with benzoyl or tartaric acid.
Additionally, the literature proposed a method for racemization of the undesired enantiomer in MTBE (Astleford, B. A.; Weigel, L. O. Resolution Versus Stereoselctive Synthesis in Drug Development: Some Case Studies. In Chirality in Industry II: Developments in the Comercial Manufacture and Applications of Optically Active Compounds; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; John Willey & Sons: Chichester, 1997; pp 99-117). The process described herein can require substantial work-up, and a change of solvents before the chiral resolution process.
In order to get the maximum yield in the preparation of (S)-AT-OL, there is a need in the art for an improved and efficient synthetic route for the preparation of (S)-AT-OL. The processes of the prior art result in a relatively high amount of (R)-AT-OL. Furthermore, the processes of the art lack a continuous one pot process that efficiently recycles (R)-AT-OL, using the initial solvent system used for the chiral resolution.